Prostate cancer is one of the most common causes of cancer deaths in American males. In 2007, approximately 219,000 new cases are expected to be diagnosed as well as 27,000 deaths due to this disease (NCI SEER data; Cancer Facts and Figures, American Cancer Society). There are currently very limited treatment options for prostate cancer patients once the cancer has metastasized (spread beyond the prostate). Systemic therapy is primarily limited to various forms of androgen (male hormone) deprivation. While most patients will demonstrate initial clinical improvement, virtually inevitably, androgen-independent cells develop. Endocrine therapy is thus palliative, not curative. (Eisenberger M. A., et al. (1998) NEJM 339:1036-42). Median overall survival in these patients where androgen-independent cells have developed was 28-52 months from the onset of hormonal treatment (Eisenberger M. A., et al. (1998) supra.). Subsequent to developing androgen-independence, only taxane-based (i.e., docetaxel) chemotherapy has been shown to provide a survival benefit, with a median survival of 19 months. Once patients fail to respond to docetaxel, median survival is 12 months.
Where prostate cancer is localized and the patient's life expectancy is 10 years or more, radical prostatectomy offers the best chance for eradication of the disease. Historically, the drawback of this procedure is that many cancers had spread beyond the boundaries of the operation by the time the cancers were detected. However, the use of prostate-specific antigen (PSA) testing has permitted early detection of prostate cancer. As a result, surgery is less extensive with fewer complications. Patients with bulky, high-grade tumors are less likely to be successfully treated by radical prostatectomy. Radiation therapy has also been widely used as an alternative to radical prostatectomy. Patients generally treated by radiation therapy are those who are older and less healthy and those with higher-grade, more clinically advanced tumors. However, after surgery or radiation therapy, if there are detectable serum PSA concentrations, persistent cancer is indicated. In many cases, PSA concentrations can be reduced by radiation treatment. However, this PSA concentration often increases again within two years signaling disease recurrence.
For treatment of patients with locally advanced disease, hormonal therapy before or following radical prostatectomy or radiation therapy has been utilized. Orchiectomy (removal of the testicles) reduces serum testosterone concentrations, while estrogen treatment has a similar effect.
Prostate Specific Membrane Antigen (PSMA) is present on the cell surface of some normal prostatic epithelial cells, normal renal proximal tubular cells, proximal small bowel and some astrocytes (found in the brain). PSMA is highly upregulated/overexpressed on prostate cancer (Pca) cells. Expression levels of PSMA increase along with prostate cancer progression and higher PSMA levels in early stage Pca predict a higher likelihood of recurrence.
Furthermore, virtually all solid tumors express PSMA in their tumor neo-vasculature whereas normal vascular endothelium is PSMA-negative.
Monoclonal antibodies which recognize PSMA have been developed, including 7E11, which binds to the intracellular domain. (Horoszewicz et al. (1987) Anticancer Res. 7:927-936; U.S. Pat. Nos. 5,162,504; 6,107,090; 6,150,508; and 7,045,605), and other anti-PSMA antibodies that bind the extracellular domain.
Cancer treatments often include administering therapeutic agents that have adverse or otherwise undesirable side effects, including toxicity. Further, the effect of a given treatment on the cancer of an individual patient is variable. In some patients, the given treatment can be highly effective, while in others, it can have little or no effect on the cancer. Furthermore, because of unpredictable and variable treatment outcomes, clinical trials must be very large to reach statistical significance. Large clinical trials can become prohibitively expensive or otherwise impracticable. Therefore, there is a need for improved treatments that mitigate toxicity, improve likelihood of a favorable outcome, and to facilitate clinical trials.